The present invention relates to ophthalmic preparations and more specifically relates to ophthalmic preparations for use as a tear film supplement, wherein the preparation comprises a mucin component.
Initial descriptions and models of the tear film described the tear film as including three distinct layers and as being a three-layered, aqueous-dominated tear film. One of the layers comprises a mucin layer which serves primarily to render the hydrophobic ocular surface hydrophilic, so that the aqueous layer comprising the bulk of the tear film will spread evenly over the eye.
Current work in this field has shown that the classic aqueous-dominated tear film model has been replaced by the more probable concept of a mucin-dominated gel. This gel has its highest concentration of mucin at the epithelial surfaces of the cornea and conjunctiva, and the mucin concentration gradually decreases farther out into the tear film. In this model, the presence of mucin remains significant for the structure, stability and function of the entire tear film. Recent studies of the tear film using laser interferometry and confocal microscopy might be including the entire gel layer in indicating that the human tear film is 30 to 40 microns thick, more than four times thicker than earlier estimates.
Based on tear film physiology and clinical observations, tear film abnormalities are commonly designated by focus on a specific deficiency, such as an aqueous tear deficiency, keratoconjunctivitis sicca (KCS), a mucin deficiency, a lipid abnormality, an impaired lid function, or an epitheliopathy. Although clinically useful, the simplistic concept of a lack of one component of the tear film as the cause of dry eye has given way to a much more sophisticated view of ocular surface disease that involves: (1) the health and regulation of the various glands contributing secretions to the tear film, (2) changes in the tear film itself, such as in osmolality and content of inflammatory mediators, and (3) what is viewed as a sort of xe2x80x9cfinal common pathwayxe2x80x9d, the subsequent changes to the ocular surface. In fact, many clinicians and authors prefer the term xe2x80x9cocular surface diseasexe2x80x9d over xe2x80x9cdry eyexe2x80x9d, for it is change to the ocular surface, whatever the original cause, that results in the significant signs and symptoms of dry eye. The discomfort of ocular surface disease is expressed in ocular symptoms, such as dryness, grittiness, burning, soreness or scratchiness, with variation among individuals. These symptoms can also be exacerbated by factors such as environmental conditions and contact lens wear. The combination of varying clinical signs and symptoms has also been termed dry eye syndrome.
Over the past twenty to thirty years many attempts have been made to provide an effective and long lasting treatment of dry eye symptoms, particularly for patients with moderate to severe KCS. These prior art attempts can be categorized on the basis of their physical state: ointments, emulsions, solid devices and aqueous based solutions or gels. Ointments are generally anhydrous preparations based on mixtures of white petrolatum and mineral oil. Because these formulations are greasy and cause blurred vision, they are not widely used other than in cases of severe symptoms, and are mostly limited to application at night just before sleeping. Emulsion based formulations for treating dry eye symptoms have emerged over the past ten years. One approach has been disclosed in a series of U.S. Pat. Nos. 5,578,586; 5,371,108; 5,294,607; 5,278,151; 4,914,088, all of which are herein incorporated by reference in their entirety. These patents teach the methods and compositions for reducing evaporation of the aqueous layer from the surface of the eye. The method comprises applying an admixture of a charged phospholipid and a non-polar oil over the eye, preferably in the form of a finely divided oil-in-water emulsion. Another approach is described in U.S. Pat. Nos. 4,818,537 and 4,804,539, incorporated herein by reference in their entirety, where liposome compositions in the form of emulsions are claimed to provide enhanced retention on ocular surfaces and thereby alleviate the symptoms of dry eye.
Solid devices, in the form of ocular inserts, have been utilized for longer term symptomatic relief of dry eye. These devices are placed in the eye and slowly dissolve or erode to provide a thickened tear film. Often patients find these devices difficult to insert and once in place, they tend to be uncomfortable. Examples of this technology are given in U.S. Pat. Nos. 5,518,732; 4,343,787, and 4,287,175, all of which are incorporated by reference in their entirety.
The most recommended and commercially successful methodology to treat dry eye symptoms is aqueous based solutions or gels. For the patient, eye drops are convenient and easy to apply relative to the other options mentioned above. There are at least thirty artificial tear products currently on the market from which to choose. For the most part the xe2x80x9cactivexe2x80x9d ingredients in these present day artificial tear formulations are common water soluble or dispersable polymers such as: hydroxyethylcellulose; hydroxypropylmethylcellulose; methylcellulose; carboxymethylcellulose; polyvinyl alcohol; polyvinyl pyrrolidone; polyethylene glycol; carbomers; and poloxamers.
These currently marketed products, while providing temporary relief of symptomsxe2x80x94usually measured in minutesxe2x80x94are strictly palliative without long term effect. In fact, to truly maintain relief of symptoms in moderate to severe cases, an impractical schedule of doses would be necessary. With preserved solutions, the frequency of instillation can lead to signs and symptoms of irritation, making it necessary to utilize expensive and more cumbersome unit dose delivery packages.
The recent patent literature indicates a continued interest in pursuing synthetic based artificial tear solutions. For example, U.S. Pat. No. 5,460,834, incorporated herein by reference in its entirety, teaches the use of hydroxypropylmethylcellulose along with other ingredients as an ophthalmic solution, and PCT publication WO98/11875, incorporated herein by reference in its entirety, discloses the use of polyvinylpyrrolidone in combination with other components to relieve eye dryness.
The art recognizes that an ophthalmic solution must provide an effective and long lasting treatment for symptoms of dry eye. One approach to achieving these aims is to provide a solution with tailored rheological properties, that is, a high viscosity solution that yields or flows under stress. Examples of this approach are disclosed in U.S. Pat. Nos. 5,075,104 and 5,209,927, incorporated herein by reference in their entirety, where the rheological properties of the ophthalmic solutions are attained through the use of carbomer polymers. These carbomer polymers have been found to be bio-adhesive as described in U.S. Pat. Nos. 5,225,196; 5,188,828; 4,983,392 and 4,615,697, all of which are incorporated by reference in their entirety. It is believed that the bio-adhesive properties of the carbomer contributes to longer retention times in the eye. In fact, U.S. Pat. Nos. 5,075,104 and 5,209,927, incorporated by reference in their entirety, teach xe2x80x9cthat the carbomer polymers appear to function by maintaining or restoring the normal hydration equilibrium of the epithelial cells, protecting the cornea in a manner similar to that believed to be provided by the mucin component of normal tears. Therefore, in theory, the polymers, in addition to being well retained in the eye and providing lubrication, can function as a mucin substitute in the dry eye syndrome where there is a deficiency or absence of the natural mucin component of the normal tearsxe2x80x9d.
Polymers that exhibit mucin-like properties are often referred to as xe2x80x9cmucomimeticxe2x80x9d. Usually in the art the mucin-like property provided by such xe2x80x9cmucomimeticxe2x80x9d polymers is simply viscosity. While it is true that a viscous solution will stay in the eye somewhat longer, it is the viscoelasticity, rather than simply the viscosity, of the gel-forming mucin of the tear film that is critical to its protective function during blinking. Additional lubrication and protection from drying and physical trauma to the ocular surface itself comes from the transmembrane mucin expressed on the surface of the entire ocular surface epithelium. It has also been proposed that this transmembrane mucin plays a critical role in spreading and maintaining the tear film structure through its interaction with the secreted gel-forming mucins of the tear film.
Mucins are the most important component in the tear film for promoting lubrication during the blinking process. The rate of shear during blinking can be very high. At such levels damage to cells and subsequent pain will occur if the shearing forces generated during blinking are transmitted to the epithelial surfaces. Two rheological conditions can mitigate the action of the shearing forces due to blinking. Firstly, shear thinning (non Newtonian behavior) of the tear film as the shear forces increase will result in a reduction of the apparent viscosity. Secondly, the energy associated with the shear forces can be partially absorbed by the elastic component of the tear film. These rheological conditions are provided by the viscoelastic properties of ocular mucin secretions, both in the gradient concentration of the fluid layer and in the gel near the epithelial surface. As a result, during eye movement the mucin can act on the stress gradient across the tear film and reduce the shear forces to near zero at the cell surfaces. Current commercial artificial tear products do not achieve the viscoelastic properties of human tears and have very limited retention time and lubricity effect in the eye.
The search for mucin-like polymers has extended into the area of bio polymers, with particular emphasis on the naturally occurring polysaccharides. One polymer, hyaluronic acid, and its sodium salt have received much attention over the past several years. In fact, one commercial product, Hylashield(copyright), based on a high molecular weight sodium hyaluronate, has been successfully marketed as a dry eye treatment solution. The use of hyaluronic acid in artificial tear solution compositions is also taught in U.S. Pat. Nos. 5,470,628; 5,460,834 and 5,106,615, all of which are incorporated by reference in their entirety. Other polysaccharides, such as carrageenan, tamarind gum and keratan sulfate have been claimed to have utility in artificial tear solutions as disclosed in U.S. Pat. Nos. 5,403,841 and 5,460,834 and PCT publications WO97/28787, all of which are incorporated by reference in their entirety. In addition, polysaccharides, such as alginate, dextran, scleroglucan and xanthan have been used, or have been proposed for use in ophthalmic solutions.
Prior art clearly recognizes the importance of mucin in the natural tear fluid as a wetting agent, viscoelastic gel former, lubricant and barrier to bacterial adhesion. Limited success with so many various synthetic and substitute polymers indicate that supplementing the tear fluid with a compatible mucin from an exogenous source would appear to be a more direct and preferred method for addressing dry eye conditions. Part of the problem in the development of ocular surface changes in dry eye disease may be the dehydration of the mucus gel and subsequently the mucin layer of the cellular surface. Supplementing the tear fluid with mucin in an aqueous solution would be expected to help maintain the natural surface mucin layer of the eye by both the addition of the additional mucin molecules and the hydration provided by the aqueous vehicle.
Perhaps one reason that mucin-based ophthalmic solutions have not been developed is the limited commercial availability of mucin. The mucins that are available are partially purified from bovine submaxillary glands, or from porcine guts. These by-products of the meat packing industry are distributed by Sigma Chemical Company (St. Louis, Mo.) and Worthington Biochemical Corp. (Freehold, N.J.). The most notable problem with currently available commercial mucins is their very poor quality. For example, fractionation of BSM mucin from Sigma by SDS-PAGE reveals that the preparation is heavily contaminated by low molecular weight proteins that are either degraded mucin, or proteins unrelated to mucin.
The patent literature reveals one reference to the use of mucin in sterilized, preserved and stable solutions. U.S. Pat. No. 4,438,100, incorporated by reference in its entirety, describes mucin-containing solutions for application to sensitive mucous membranes of the oral cavity, the nasal system and the eye. The mucins utilized in this invention are non human mammalian mucins selected from the group consisting of buccal and gastrointestinal mucins. In fact, the source of their mucins is mucus, a mature and complex secretion containing a mixture of various mucin molecules as well as other proteins and associated contaminants of secretion. The is no distinction made between secreted mucins and mucins expressed by the surface cells of the oral cavity or gastrointestinal mucous membranes. The inventors provide examples of mucin-containing solutions for use as artificial saliva, but do not teach the preparation of ophthalmic solutions. In fact, the inventors discuss the potential use of mucin-containing ophthalmic solutions in conjunction with contact lens care. It is evident that the inventors did not contemplate the use of mucin as a tear supplement.
The present application is directed to ophthalmic preparations for use as a tear film supplement. More specifically, this application relates to an aqueous formulation to be instilled into the eye, or in which to pre soak or store an object to be inserted into the eye, such as a contact lens, an ointment, or a solid device to be inserted into the conjunctival sac. The preparations disclosed are utilized for the treatment of disorders such as keratoconjunctivitis sicca or dry eye syndrome. In general, the preparations are also effective for the relief of symptoms of eye irritation, such as those caused by dry environmental conditions or by contact lens wear.
In particular, the present application relates to ophthalmic compositions comprising a mucin component, similar to that found at the normal human ocular surface, as well as to methods for their preparation and storage. The application also relates to a method of treating the eye by topically applying the composition of the present invention, when indicated, to provide lubrication and protection of the ocular surface, for the relief of dryness and discomfort symptoms, such as experienced in patients with dry eye and following traumatic injury or surgery, and when indicated to achieve the other effects mentioned above. In one preferred embodiment the compositions of the present invention are provided as buffered, sterile aqueous solutions. The subject compositions may be unpreserved (provided in a unit dose format) or may be preserved.
In one embodiment, the mucin component is a transmembrane or surface mucin (e.g., those mucins classified as MUC1 or MUC4) and is expressed at the epithelial surface of various mucosal, glandular and ductal organs and tissues in mammals. Such organs and tissue include the ocular surface, mammary glands, salivary glands, esophageal epithelium, stomach, pancreas, bile ducts, lung epithelium, kidneys, bladder, and the uterus. Mucous membranes are found in the bucal and nasal cavity surfaces as well as the gastrointestinal, tracheobronchial and reproductive tracts. As a result of its expression in the mammary gland epithelium of mammals, MUC1 is a surface component of the fat globules in secreted mammalian milk. To form the exemplary ophthalmic preparations disclosed herein, other ingredients commonly employed in ophthalmic formulations are utilized to provide a balance of physiologically acceptable properties, depending on whether the final product is a solution, ointment, gel or solid.
The above-discussed and other features and advantages of the present invention will be appreciated and understood by those skilled in the art from the following detailed description.
Mucins refer to a family of glycoproteins of high molecular weight, secreted or expressed by goblet and nongoblet epithelial cells of mucosal tissues. These mucins predominate in the formation of mucus, a highly hydrated gel of particular structure and function. Mucins are heavily glycosylated high molecular weight glycoproteins with predominantly O-linked oligosaccharide side chains. Mucin molecules are generally above 200 Kda, with carbohydrate composing 50% or more of their dry weight. At least nine distinct mucin genes have been identified (MUC1, 2, 3, 4, MUC5AC, MUC5B, MUC6, 7 and 8). Furthermore, each of these is produced in various forms in different tissues. This suggests that the mucins serve unique, tissue-specific protective functions at the apical surfaces of specialized epithelial cells. MUC1, the so-called xe2x80x9cepithelial mucinxe2x80x9d, is a membrane-spanning mucin found in abundance in epithelial tissues. MUC1 is known by various other names, such as polymorphic epithelial mucin or episialin. MUC1 has a molecular weight in the 125 to 225 KDa range, which is low when compared to the other types of mucin.
In the human eye, the secretory mucins MUC2 and MUC5AC have been detected (via transcripts at the nucleic acid level) from conjunctival isolates, and only MUC5AC has been localized to conjunctival goblet cells. The transmembrane mucin MUC1 is associated with the cell membranes of the entire corneal and conjunctival epithelial surface, except the goblet cells. Another transmembrane mucin is the mucin MUC4, which is associated with the cell membranes of the entire conjunctival epithelial surface, except the goblet cells. Qualitative and quantitative analyses of ocular mucins are difficult because there are as yet no specific probes for individual ocular mucins, and little is known about the mechanisms or extent of synthesis or secretory regulation of these mucins. One or more calcium dependent processes are possible, with involvement of several secretagogues, such as prostanoids, autonomic transmitters, and neuropeptides being investigated.
The secreted ocular mucins are relatively large molecules, and have a significant role in the gel-forming nature of the tear film. The model of the greater part of the tear film being a highly hydrated mucus gel, rather than simply a watery aqueous layer, is becoming increasingly accepted. The viscoelasticity of the tear film derives from the specific structure and gel-forming properties of the ocular mucins, and allows the tear film to absorb the shear force of the blink, which would otherwise irritate and damage the ocular surface. The transmembrane mucin, on the other hand, serves more as a protective layer on the actual cellular surface of the ocular epithelium, functioning to directly protect and lubricate the ocular surface, as well as to anchor the highly hydrated gel (mucus) of the tear film gel-forming mucins, thereby assisting in the spreading and stability of the tear film over the ocular surface.
Stratified layers of the above mucins are known to form over the surface of mucosal membranes, such as in the gut, affecting the flow and interaction of the protective layer and its contents with the cellular surface of the epithelium. A difficiency in one type of mucin would therefore be expected to affect the lubricating, protective, barrier and other functions of the other mucins at the mucosal surface.
In a mild to moderate dry eye, the goblet cell density is not significantly reduced, indicating that MUC5AC is most likely still able to be produced normally, in quantities sufficient to be spread over the entire ocular surface. However, localized early ocular surface changes resulting from dryness, such as that revealed by fluorescein or rose bengal staining, can be seen in the epithelia of the corneal and conjunctival surfaces. This localized damage to the ocular surface indicates that even marginal dryness might have a significant effect on the presence of functional MUC1 on the surface of the ocular epithelium. Since one of the proposed functions of MUC1 is to help the other, more abundant gel-forming ocular mucins adhere to the ocular surface, a paucity of MUC1 might significantly affect the stability of the tear film, even in the presence of an abundance of MUC5AC secreted by the conjunctival goblet cells. When investigated using the technique of impression cytology, the more severe ocular surface changes resulting from dryness, exhibited in the process of squamous metaplasia, are also seen to occur initially in localized areas. These more pathological localized surface changes are further evidence for a critical protective role of MUC 1. There is some early evidence that with the progression of changes to the ocular surface mucins associated with dry eye, as detected by immunohistochemical methods, the goblet cells themselves try to make up for the lack of normal expression of MUC1 by the rest (non goblet cells) of the corneal and conjunctival surface epithelium, and begin expressing a MUC1-like molecule in their secretions.
Although not being held to any one theory we believe that the particular type of mucin described in this invention, being a transmembrane or surface mucin, acts to protect and lubricate the ocular surface, as in the role of the natural transmembrane mucins, MUC1 and MUC4, which is expressed by the entire surface epithelium of the conjunctiva and cornea. By supplementing the natural epithelial surface mucin, the lubrication and protection of the ocular surface is enhanced, in order to slow the progression, and associated development of symptoms, of changes to the ocular surface epithelium, such as decreased tear film stability, increased staining with fluorescein sodium or rose bengal, decreased goblet cell density and the development of squamous metaplasia seen with ocular surface disease. The property of viscosity in the preferred embodiment is primarily targeted to assist in retention of the invention in the eye at the ocular surface, as well as for lubrication and comfort associated with instillation. Viscosity is not the physical property which gives the mucin formulation of this invention its xe2x80x9cmucomimeticxe2x80x9d function. This invention primarily protects and lubricates the ocular surface and interacts with the gel-forming secreted mucins of the tear film, thereby enhancing the spreading of the tear film, and by default of instillation adds to the tear film volume and hydration of the ocular surface. The xe2x80x9cmucomimeticxe2x80x9d effects of this invention, therefore, are those of the transmembrane mucin expressed on the ocular surface epithelium, and not the gel-forming mucins secreted by the goblet cells. Together, these effects protect the ocular surface from dryness and absorb shear forces of the blink, and assist the eye""s own secreted gel forming mucins (predominantly MUC5) in maintaining their viscoelastic properties and ensuing structure and stability of the tear film, thereby slowing or preventing the changes to the ocular surface seen in dry eye conditions.
Although mucins can be obtained from various sources, they have similar structures for the particular molecules described above (MUC 1, 2, etc.) among species, particularly with regard to the protein backbone. They are glycoproteins containing from fifty to eighty percent carbohydrate. They are large, elongated molecules (molecular weight 105 to 107 daltons) with a protein backbone to which oligosaccharides are attached in a bottle-brush configuration. The oligosaccharide side chains, or bristles, can be highly variable in their make-up, indicating that the more basic functions of the molecule derive from the protein core. These molecules can be crosslinked through disulfide bridges to form very high molecular weight gels. MUC1 and MUC4, the surface or transmembrane mucin molecules, are the smallest mucins and are not considered gel forming mucins on their own, although cleaved parts of the molecules can be found in soluble form.
The mucins used in exemplary ophthalmic compositions are of the MUC1 and MUC4 type, and are derived from the surface of glandular and ductal epithelial cells. Such mucin can be collected by extracting it from the tissue, either by subjecting the surface or its associated secretion, such as bile or saliva, to liquid extraction or by mechanical (scraping) means. From the research on its role in tumor cell proliferation, more is known about MUC1. Mucin of the MUC1 type can also be derived from tumor cell lines, such as colon carcinoma. MUC1 can also be isolated from mammalian milk, particularly bovine, or milk byproducts, such as whey.
Recovery and purification of MUC1 from its source can be carried out utilizing standard methods known in the art. Published studies on the structure and function of mucin have led to several preferred isolation techniques. These would include, but are not limited to, cell disruption, membrane filtration and microfiltration, tangential flow filtration, chromatography (e.g., size exclusion, ion exchange, affinity), extraction, adsorption, precipitation (with nonsolvent, salts, etc.) density gradient fractionation, electrophoresis, electrodialysis and isoelectric focusing. The MUC1 that results can be in the form of a hydrocolloid, which is a complex of the MUC1 linked to lower molecular weight proteins through disulfide bridges. This complex molecular structure contains from about fifty percent to seventy percent or higher MUC1, and may contain a lipid component as well.
The scientific literature reveals a number of techniques for characterizing the various types of mucins, and in particular MUC1. These techniques include, but are not limited to, chromatographic techniques or gel electrophoresis, particularly SDS-PAGE, followed by direct protein staining, (e.g., silver staining) or immunohistochemical staining (e.g., Western blotting or Northern blotting), and immunoprecipitation techniques, amino acid analysis, hexosamine and hexuronic acid determination, carbohydrate determination, lectin binding probes, such as jaclin, light scattering, scanning electron microscopy, mass spectrometry, mucin nitrogen content and ash.
The amount of mucin in an ophthalmic formulation can vary greatly depending on the product type. For example, in contact lens related solutions the mucin concentration would vary from about 0.001% to 5.0% by weight. In dry eye preparations the mucin level could vary from about 0.1% to about 10.0% by weight. In a solid ocular insert delivery device the mucin level could range to about 90.0% or greater by weight. Within each type of preparation, the concentration might be varied, depending on such factors as the severity of the dry eye condition being treated, to enhance particular properties of the mucin solution. These ranges are for purpose of illustration and are not meant in any manner to limit the scope of the claims.
Exemplary ophthalmic compositions include a transmembrane or surface mucin (e.g., MUC1 or MUC4) from any number of the exemplary sources described hereinbefore. In addition, other solution components may be employed as required:
Viscosifiers
Cellulose derivatives are commonly used to increase viscosity. Specific cellulose derivatives include: hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, etc. Some polysaccharides may also be utilized to increase the viscosity of ophthalmic solutions and include xanthan, scleroglucan, carrageenans, tragacanth gum, hyaluronic acid etc. Other viscosifiers that are useful include polyvinylpyrrolidone, polyvinyl alcohol, polyethyleneoxide, polyacrylic acid and crosslinked polyacrylic acid. Generally, viscosifiers are present in the amount of 0.1 to 0.75% by weight of the solution.
Buffering Agents
Any pharmaceutically acceptable buffer system may be utilized and include phosphates, borates, citrates, acetates and carbonates in amounts necessary to produce a pH of about 6.0 to about 8.0.
Tonicity Agents
The tonicity of the ophthalmic solutions described here can be adjusted to either hypotonic, isotonic or hypertonic relative to normal tears by use of generally used materials know to the art. Sodium and potassium chloride are widely used to adjust tonicity. Other agents include dextrose, mannitol, sorbitol and urea.
Humectants
Water binding compounds aid in retaining moisture on the ocular surface and include glycerin, propylene glycol, polyethylene glycol.
Wetting Agents
Certain compounds are useful to promote surface wetting, whether it be the ocular surface or the surface of a contact lens. One category that is preferred is the polyoxamers. These polyethyleneoxide-polypropyleneoxide-polyethyleneoxide block copolymer are available from BASF. Other compounds include the Tetronics(copyright), reverse Pluronics(copyright) and the reverse Tetronics(copyright), also available from BASF.
Preservatives
The exemplary compositions may include a preservative in an effective amount. Preservatives known to the art include alkyldimethyl benzylammonium chloride (BAK), chlorhexidene gluconate (CHG), polyhexamethylene biguanide (PHMB), other polyquats and sorbic acid. The exemplary compositions may also include a co-preservative and/or chelating agent, such as ethylenediaminetetraacetic acid (EDTA) and its salts.
Other Additives
In some cases it may be beneficial to include other components in an ophthalmic solution. These include specific ions, such as Ca++, Zn++ and Mg++, Cu++, selenium, vitamins, such A, C and E, to promote ocular health. The exemplary ophthalmic compositions described herein may also be utilized as vehicles for drug delivery. Drugs often used in the eye include anti-glaucoma compounds, anti-inflammatory agents and anti-infective agents.
Examples of ophthalmic drugs include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, tobramycin, gentamicin, erythromycin and penicillin; antibacterials such as sulfonomides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals including idoxuridine, trifluorothymidine, acyclovir, gancyclovir and interferon; non-antibiotic, anti-infection, anti-bacterial or anti-microbial drugs such as iodine based preparation triclosan, chlorhexidine, et al; anti-allergenics such as sodium cromoglycate, antazoline, methapyrine, chlorpheniramine, cetirizine and prophenpyridadine; anti-inflammatories such as hydrocortisone, hydrocortisoneacetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolone, medrysone, prednisolone acetate, luoromethalone, hypothalamus releasing factor; beta adrenergic blockers such as timolol maleate, levobunclol HCl and betaxolol HCl; growth factors such as epidermal growth factor and fibronectin; carbonic anhydrase inhibitors such as dichlorphenamide, betamethasone, and triamcinolone and non-steroidal agents such as indomethacin, diclofenac, flurbiprofen, piroxicam, ibuprofen and acetylsalicylic acid; decongestants such as phenylephrine, naphazoline and tetrahydrozoline: miotics and anticholinesteras such as pilocarpine, acetylcholinechloride, physostigmine, eserine, carbachol, di-isopropylfluorophosphate, phospholineiodine, and demecarium bromide; mydriatics such as a tropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics such as epinephrine; immunological drugs such as vaccines and immunostimulants; hormonal agents such as estrogens, estradiol, progestational, progesterone, insulin, calcitonin, parathyroidhormone and peptide, vasopressin, acetazolamide and methazolamide and other drugs such as prostaglandins antiprostaglandins, and prostaglandin precursors; angiogenesis inhibitors such as liferative agents such as flurouracil and mitomycin.
As previously described, the exemplary ophthalmic compositions finds particular utility as lubricating eye drops, i.e., an artificial tear solution, a tear fluid supplement, a delivery vehicle for topical ophthalmic drug application. In most of these applications, the compositions are provided in a buffered, sterile aqueous solution. Typically, these solutions have a viscosity from about 1 to 100 cps. As a solution the compositions are dispensed in the eye in the form of an eye drop. It should be understood, however, that the compositions described herein may also be formulated as viscous liquids, i.e., viscosities from several hundred to several thousand cps, gels or ointments. In these applications the mucin component would be dispersed or dissolved in an appropriate vehicle such as Lubragel, GRR Lubricating Jelly or Karajel, all trademarked products of United-Guardian, Inc., Hauppauge, N.Y.
The exemplary compositions may also be formulated as solid ocular inserts that dissolve or erode over time when placed in the cul-de-sac of the eye.
Swelling-controlled release devices would consist of mucin homogeneously dispersed in a glassy polymer such as a water soluble cellulosic. When the insert is placed in the eye, the tear fluid begins to penetrate the matrix, followed by swelling, and finally dissolution, of the matrix. As this process occurs, mucin is released into the eye to provide relief of dry eye symptoms over a long period of time.
Erodible devices would again consist of mucin homogeneously dispersed in a polymer matrix. In this case, mucin is released by a chemical reaction (hydrolysis) that results in solubilization of the matrix polymer, usually at the surface of the device. Generally, the matrix material is a polyanhydride or a poly(ortho ester).
In another embodiment the mucin may be chemically modified or crosslinked to act as its own xe2x80x9cmatrixxe2x80x9d, where mucin comprises the entire, or nearly entire, device, thus providing the maximum amount of mucin available to the eye.
Furthermore, in some contact lens related embodiments, the exemplary transmembrane or surface mucin disclosed herein may be incorporated into contact lens soaking and conditioning solutions as well as lubricating eye drops for contact lens wearers.
In another embodiment the mucin may be utilized in drug delivery. The most common and convenient method for delivery of ocular drugs is by way of topical eye drops. Generally, the solution vehicles employed are quickly diluted by the tear fluid and drain from the eye in a matter of minutes. This short residence time hinders the absorption and hence the bioavailability of the drug in the eye. Oftentimes the short residence time is overcome by greatly increasing the concentration of the drug to improve bioavailability. This often leads to significant undesirable side effects due to the systemic actions of many of the ocular drugs currently prescribed.
Much research has been done to improve the residence time of the drug vehicle at the ocular surface and also to promote interaction or association of the drug with the vehicle. One approach that has been commercialized is to utilize a crosslinked carboxy-functional polymer such as Carbopol(copyright), supplied by B.F. Goodrich. The bioadhesive nature of this polymer has been the basis for controlled release ophthalmic formulations as described in U.S. Pat. No. 4,615,697 and U.S. Pat. No. 5,188,826, both of which are incorporated by reference in their entirety.
These crosslinked carboxy-functional polymers swell in aqueous solution but remain as micron-size hydrated particles. Furthermore, at neutral pH, they are substantially anionic in nature. Since many ophthalmic drugs, for example timolol and pilocarpine, are positively charged, they will associate with the negatively charged polymer particles through electrostatic interaction. Also, since the hydrated particles are microporous, the drug can be absorbed into the matrix. When an ophthalmic solution of this type is placed in the eye, the hydrated polymer particles adhere to the mucosal surface, providing extended residency time. During this residence the drug is released from the hydrated polymer particles, thus providing for a more efficient local delivery to the eye.
The transmembrane or surface mucins, MUC1 and MUC4, used in the exemplary compositions are by definition xe2x80x9cbioadhesivexe2x80x9d and contain multiple negative charges. It has also been shown that the mucins of this invention can exist as hydrocolloid particles. Given this information one would expect the mucins of this invention to act in a similar manner to the crosslinked carboxy-functional polymers as an ophthalmic drug delivery vehicle. In practice, these transmembrane or surface mucins provide superior retention time due to their ability to interact not only with the epithelial surface but also with the natural mucins in the tear film.
As an illustration of the exemplary mucin-containing compositions, several examples are provided below. A key to the ingredients used in the Examples is given in Table I.